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The Journal of Neuroscience, August 6, 2008, 28(32):8074-8085; doi:10.1523/JNEUROSCI.4904-07.2008

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Behavioral/Systems/Cognitive
Impaired Fear Extinction Learning and Cortico-Amygdala Circuit Abnormalities in a Common Genetic Mouse Strain

Kathryn Hefner,^1 * Nigel Whittle,^2 * Jaynann Juhasz,¹ Maxine Norcross,¹ Rose-Marie Karlsson,¹ Lisa M. Saksida,³ Timothy J. Bussey,³ Nicolas Singewald,² and Andrew Holmes¹

¹Section on Behavioral Science and Genetics, Laboratory for Integrative Neuroscience, National Institute on Alcoholism and Alcohol Abuse, National Institutes of Health, Rockville, Maryland 20852, ²Department of Pharmacology and Toxicology, Institute of Pharmacy and Center for Molecular Biosciences Innsbruck, University of Innsbruck, A-6020 Innsbruck, Austria, and ³Department of Experimental Psychology and Medical Research Council and Wellcome Trust Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge CB2 3EB, United Kingdom

Correspondence should be addressed to Dr. Andrew Holmes, Section on Behavioral Science and Genetics, Laboratory for Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, 5625 Fishers Lane, Room 2N09, Rockville, MD 20852-9411. Email: holmesan{at}mail.nih.gov

Fear extinction is a form of new learning that results in the inhibition of conditioned fear. Trait deficits in fear extinction are a risk factor for anxiety disorders. There are few examples of naturally occurring animal models of impaired extinction. The present study compared fear extinction in a panel of inbred mouse strains. This strain survey revealed an impairment in fear extinction in 129/SvImJ (129S1). The phenotypic specificity of this deficit was evaluated by comparing 129S1 and C57BL/6J for one-trial and multitrial fear conditioning, nociception, and extinction of conditioned taste aversion and an appetitive instrumental response. 129S1 were tested for sensitivity to the extinction-facilitating effects of extended training, as well as D-cycloserine and yohimbine treatment. To elucidate the neural basis of impaired 129S1 fear extinction, c-Fos and Zif268 expression was mapped after extinction recall. Results showed that impaired fear extinction in 129S1 was unrelated to altered fear conditioning or nociception, and was dissociable from intact appetitive extinction. Yohimbine treatment facilitated extinction in 129S1, but neither extended extinction training nor D-cycloserine treatment improved 129S1 extinction. After extinction recall, 129S1 showed reduced c-Fos and Zif268 expression in the infralimbic cortex and basolateral amygdala, and elevated c-Fos or Zif268 expression in central nucleus of the amygdala and medial paracapsular intercalated cell mass, relative to C57BL/6J. Collectively, these data demonstrate a deficit in fear extinction in 129S1 associated with a failure to properly engage corticolimbic extinction circuitry. This common inbred strain provides a novel model for studying impaired fear extinction in anxiety disorders.

Key words: fear; extinction; anxiety; gene; prefrontal cortex; amygdala; intercalated cell masses

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Received Oct. 30, 2007; revised June 5, 2008; accepted June 25, 2008.

Correspondence should be addressed to Dr. Andrew Holmes, Section on Behavioral Science and Genetics, Laboratory for Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, 5625 Fishers Lane, Room 2N09, Rockville, MD 20852-9411. Email: holmesan{at}mail.nih.gov

Related articles in J. Neurosci.:

Neural Correlates of Individual Variability in Fear Extinction

Francisco Sotres-Bayon, Kevin A. Corcoran, Jamie Peters, and Demetrio Sierra-Mercado
J. Neurosci. 2008 28: 12147-12149. [Full Text]  

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				J. Xu, Y. Zhu, A. Contractor, and S. F. Heinemann mGluR5 Has a Critical Role in Inhibitory Learning J. Neurosci., March 25, 2009; 29(12): 3676 - 3684. [Abstract] [Full Text] [PDF]

				F. Sotres-Bayon, K. A. Corcoran, J. Peters, and D. Sierra-Mercado Neural Correlates of Individual Variability in Fear Extinction J. Neurosci., November 19, 2008; 28(47): 12147 - 12149. [Full Text] [PDF]

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